9//10-secoprogesterones



mama

3,027,409 Patented Mar. 27, 1962 United States PatentOfiice to give the corresponding 3-alkoxy-9//10-seco-1,3,5(10)- pregnatriene-11,20-dione (II), ketalizing the said 3-alkoxy steroid to produce a separable mixture of 3-al koxy-9//10- seco-1.3,5(10)-pregnatriene 11,20 dione 11,20-diketal 3,027,409 9//10-SECOPROGESTERONES John A. Hogg, Kalamazoo Township, Kalamazoo County, and Barney J. Magerlein, Kalamazoo, Mich, asslgnors to The upjuhn Company, Kalamazoo Mich, a comm 5 and the corresponding 20-monoketal (III), reducing the ration of Michigan No Drawing. Filed May 19, 1958, Ser. No. 735,998 4 Claims. (Cl. 260-586) said ZO-monoketal steroid to yield 11a-hydroxy-9//10- secoprogesterone 20*ketal) (IV), oxidizing the said 11ahydroxy-ZO-ketal steroid to give 11-keto-9//10-seco- The present lnvention relates to novel stero1d compounds and a process for their preparation and is more particularly concerned with 11-oxygenated-9//l0-secoprogesterone and intermediates and process for the production thereof.

This application is a continuation-in-part of applicants copending application Serial No. 559,778, filed January 18, 1956, now US. Patent No. 2,835,698.

The products and process of the present invention may be represented by the following reaction scheme:

CH3 CH3 c=o I no CH3 1 VIII h VII wherein R is an alkyl group containing from one to eight carbon atoms, inclusive. droxy9//lO-secoprogesterone (VII).

The process of the present invention comprises, first, It is an object of the present invention to provide the alkoxylation of 3-hydroxy 9//10 seco 1,3,5 10)- 7 ll-oxygenated 9//10 secoprogesterone and a process pregnauiene-11,20-dione (I), prepared according to the for their preparation. Another object is the provision of method of said copending application Serial No. 559,778, 1104 hydroxy-9// lfi-secoprogesterone, 11;8-hydroxy-9//- obtained by oxidation of lla-hydroxy (VI) or llfi-hyseco-4-pregnene-3,ZO-dione ZO-ketal (11a-hydroxy-9/ 10- I 10 progesterone ZO-ketal (V), and reducing and hydrolyzing IO-secoprogesterone and 11-keto-9// l-secoprogesterone and a process for their production. A further object is to provide 11-oxygenated-9//10-secoprogesterone 11,20- diketals and 20-mono ketals and a process for their preparation. Other objects will be apparent to those skilled in the art to which this invention pertains.

The products of the present invention, namely, 11- hydroxy-9//10-seco-4-pregnene-3,20-dione (ll hydroxy- 9/ lO-secoprogesterone) and 9/ seco 4 pregnene- 3,11,20-trione (11-keto-9//lO-secoprogesterone) possess progestational, luteoid, anti-estrogenic, and fungicidal activities in varying degree and in addition serve as intermediate compounds in the preparation of the 9/ lO-secohydrocortisone acylates and 9/ IO-secocortisone acylates which possess in modified degree the activities commonly associated with hydrocortisone and cortisone acylates.

In accord with applicants said copending application Serial No. 559,778, 3-hydroxy 9//l0 seco l,3,5(l0)- pregnatriene-l1,20-dione (I) is treated with an alkaline metal alkoxide wherein the alkyl group is preferably one having one to eight carbon atoms, inclusive, such as sodium methoxide, to give, in the preferred embodiment, 3*methoxy 9//lO-seco 1,3,5(l0) pregnatrlene 11,20- dione (II), which is then ketalized with an alkanediol such as ethylene glycol in the presence of minor quantities of an acid catalyst such as para-toluenesulfonic acid, according to the procedures of US. Patent No. 2,707,184. The thus obtained 3 methoxy 9//l0 seco 1,3,5( 10)- pregnatriene-ll,20-dione -ketal (III) and 11,20-diketal, preferably the ethylene ketals, are separated, if desired, and the 20-monoketal is reduced, preferably with metallic lithium in liquid ammonia and an alkanol, e.g., ethanol, to give a mixture from which 11a-hydroxy-9//10-seco progesterone ZO-ketal (IV) can be separated. Oxidation, as with acetic acid and chromic anhydride, yields ll-keto- 9//10 -secoprogesterone 20 ketal (V). The said 20- monoketal can then be reduced, preferably with lithium aluminum hydride, to give the llfi-hydroxy-9/ /10- secoprogesterone (VII). Alternatively, the said mono-ketal (V) can be hydrolyzed by any convenient hydrolysis procedure, e.g., sulfuric acid in ethanol, to produce 11- keto-9//IO-secoprogesterone (VIII). If desired, the 11ozhydIoxy-9//10-secoprogesterone ZO-ketal (IV) can in like manner he hydrolyzed to give lla-hydroxy-9//10- secoprogesterone (VI). The said 1le-hydroxy-9/ l0- secoprogesterone can then be oxidized, as with acetic acid and chromic anhydride, to yield 11 keto 9/ 10 secoprogesterone (VIII), which in turn can be converted by selective reduction, as with metallic lithium in ethanol and liquid ammonia, the l lfi-hydroxy-9//lO-secoprogesterone (VII).

The following examples are illustrative of the products and processes of the present invention but are not to be construed as limiting.

Example 1 .3-Meth0'xy -9/ O-Seco-l ,3 ,5 1 0 Pregnatriene-I1,20-Di0ne (II) To a solution of two grams of 3-hydroxy-9//10-seco- 1,3,5 (lO)-pregnatriene-l1,20-dione, dissolved in fifteen milliliters of methanol denatured alcohol and heated to seventy degrees centigrade, is added, at five-minute intervals, one milliliter of sodium hydroxide solution containing 400 milligrams of anhydrous sodium hydroxide per milliliter of water, and one milliliter of dimethyl sulfate. The additions are repeated five times and thereafter the solution is poured into water and the methyl ether extracted with methylene dichloride. After washing the methylene dichloride solution with water and drying over anhydrous sodium sulfate, the solvent is evaporated to give 2.10 grams of oily 3-methoxy-9//lO-seoo-l,3,5(l0)- pregnatriene-l1,20-dione (II) Example 2.-3-Meth0xy-9//10-Sec0-1,3,5(10)-Pregnatriene-l I ,ZO-Dione ZO-Monoethylene Ketml (III) A solution of two grams of 3-methoxy-9//l0-seco- 4 1,3,5(10)-pregnatriene-l1,20-dione in 120 milliliters of benzene, 360 milligrams of para-toluenesulfonic acid, and two grams of ethylene glycol is heated for a period of four hours at reflux temperature. Thereafter the solvent and unused ethylene glycol are removed by distillation under reduced pressure. The remaining oily liquid is the 20 monoethylene ketal of 3 methoxy 9/ l0 seco- 1,3,5 (l0)-pregnatriene 11,20 dione. Recrystallization from ethylacetate-Skellysolve B hexanes fails to convert the oil to crystalline ZO-monoethylene ketal of 3-rnethoxy- 9//l0-seco-l,3,5(l0)-pregnatriene-l1,20-dior1e (III). If desired the 1].,20-diketal of 3-methoxy 9/ l0 secol,3,5(10)-pregnatriene-11,20-dione can be separated from the ZO-ketal by chromatography.

Example 3.-] I ot-Hydr0xy-9//10-Sec0pr0gester0ne 20 Ethylene Monoketal (IV) The thus obtained 3-methoxy-9//lO-seco-l,3,5(10)- pregnatriene-ll,20-dione 20-ethylene monoketal is dissolved in fifty milliliters of ethanol and stirred thereupon into 6% milliliters of liquid ammonia. To this solution is added six grams of lithium in small pieces under rapld stir-ring. Thereafter, the reaction mixture is decomposed with milliliters of water, and evaporated under re duced pressure to a volume of milliliters. The solution is acidified with hydrochloric acid having an excess of hydrochloric acid so that a five percent acidic solu tion is obtained. This solution, containing a suspension,- is then shaken with sixty milliliters of ethyl acetate which dissolves the solids while the hydrolysis proceeds. The ethyl acetate solution is washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The remaining residue is taken up in ten milliliters of ethyl acetate and chromatographed on Florisil magnesium silicate in the same solvent. The main frac' tion from the chromatographic separation is evaporated and the solids added to a solution of thirty milliliters of ethanol containing thirty milligrams of sodium hydroxide. This mixture is kept at a temperature of fifty degrees for live minutes under a nitrogen atmosphere. After acidi' fication with a few drops of acetic acid the solvent is re moved under reduced pressure and the residue washed with water, taken up in ten milliliters, of ethyl acetate and chromatographed over alumina in ethyl acetate. The first fractions thus obtained consist of lla-hydroxy-9// 10 secoprogesterone ZO-ethylene monoketal (IV).

Example 4.] 1-Ket0-9//10-Smoprogesterone 20 Ethylene Ketal (V) A SOO-rnilligrarn portion of the solid lloz-hYtlIOXY- 9/ lO-secoprogesterone 20-ethylene monoketal is dissolved in twelve milliliters of acetic acid, and 400 milligrams of chromic anhydride is added thereto. The mixture is allowed to remain at room temperature under continuous shaking for a period of two hours. Thereafter the reaction mixture is poured onto fifty milliliters of ice and the solid l1el eto-9//ltl-secoprogesterone 20-ethylene rnonoketal (V) is collected on the filter, washed with water and recrystallized from ethyl acetate and Skellysolve B hexanes.

Example 5 .1 I u-HydrOxy-Q/ /10-Sec0pr0gesterone (VI Twenty-five milligrams of 1la-hydroxy-9//l0-secoprogesterone ZO-ethylene monoketal (IV) is dissolved in. one milliliter of ethanol containing four drops of water and one drop of sulfuric acid, and the mixture i boiled. five minutes. Thereafter the reaction mixture is neu-- tralized and evaporated to dryness. The product is washed with water and recrystallized from ethanol to give llcx-hydroxy-9// l0secoprogesterone (VI).

Example 6 .1 I/S-Hydroxy-Q/ 1 O-Secopmgesterone (VII) One gram of ll-keto-9//10-secoprogesterone ZO-ethylene monoketal, prepared as described in Example 4, is dissolved in fifty milliliters of ether and admixed thereafter with 25 milliliters of tetrahydrofuran containing 0.5

icv r winurn hydride. The mixture is heatgfam of 213 1 13 period of one hour, then cooled to g ig eratl f and diluted with 25 milliliters of 25 {31mm aqueous sulfuric acid. The thus obtained reaction mixture is heated for a period of ten minutes on the steam bath and thereafter cooled and neutralized with sodium hydroxide. The neutral solution is extracted with methylene dichloride, the extracts repeatedly washed with water, dried over anhydrous sodium sulfate and evaporated to give a solid residue. The mixture containing lloc-hydroxyand llfi-hydroxy-W/l-secoprogesterone is chromatographed to separate the isomers and obtain essentially pure l1p-hydroxy-9// 10-secoprogesterone (VII).

Example 7.]1-Ket0-9//10-Sec0pr0gester0ne (VIII) Twenty-five milligrams of 1l-keto-9// lO-secoprogesterone 20-ethylene monoketal is hydrolyzed in the manner described for the llot-hydroxy-9//lo-secoprogesterone ZO-ethylene monoketal in Example 5 to give, after recrystallization from Skellysolve B hexanes and ethyl acetate, essentially pure ll-keto-9//lO-secoprogesterone (VIII).

Example 8 .1 7ot-Hydroxy-I1[3,21-Diacel0xy-9//10-Sec0- 4-Pregnene-3,20-Di0ne (9//10-Secohydrocortisone Diacetate) Nineteen milliliters of ethyl oxalate and 21.2 milliliters of a 2.2 normal methanolic solution of sodium methoxide are added to a solution of 6.8 grams of llfl-hydroxy- 9//l0-secoprogesterone, dissolved in 100 milliliters of anhydrous tertiary butyl alcohol, at about fifty degrees centrigrade. The mixture is maintained for a period of three hours at twenty to thirty degrees centigrade, whereafter the precipitated sodium dienolate of 2,2l-diethoxyoxalyl-11fi-hydroxy-9/ lO-secoprogesterone is filtered, washed with ether and dissolved in water. The aqueous solution is acidified with dilute hydrochloric acid and the precipitate filtered therefrom and dried to give 2,21- diethoxyoxalyl 11B hydroxy-9// lO-secoprogesterohe, a yellow amorphous powder which exhibits a reddish color in alcoholic ferric chloride solution.

A solution of eight grams of 2,21-diethoxyoxalyl-1l5- hydroxy-9//10-sec0progesterone and 5.9 grams of anhydrous potassium acetate in 140 milliliters of methanol is cooled to zero degrees centigrade in an ice-bath and. a solution of 7.4 grams (0.46 mole) of bromine in 74 milliliters of methanol is added dropwise thereto over a period of about one-half hour, thus producing 2,21,21- tribromo 2,2l-diethoxyoxalyl-3-keto-1 1,8-hydroxy-9// l0- secoprogresterone. To this mixture is then added about fifty milligrams of phenol and 67 milliliters of a 1.5 normal methanolic solution of sodium methoxide. The mixture is heated for five minutes on a steam bath, then cooled and poured into water. The resulting flocculent, white precipitate of 2-bromo-1lB-hydroxy-9H IO-seco- 4,l7(20)-pregnadien-2l-oic acid methyl ester is thoroughly washed with water and dried in a vacuum desiccator. The thus produced crude 2-bromo-3-keto-11B-hy droxy-9//10-seco-4,l7(20)-pregnadien-2l-oic acid methyl ester is chromatographed from benzene, benzene-Skellysolve B hexanes and Skellysolve B hexanes and acetone. The Skellysolve B hexanes plus acetone eluates contains the desired 2-bromo-3-keto-1lp-hydroxy 9// l0 seco- 4,l7(20)-pregnadien-2l-oic acid methyl ester.

To a solution of three grams of 2-bromo-3-keto-1lfihydroxy 9// seco 4,17() -pregnadien-2l-oic acid methyl ester, dissolved in a mixture of sixty milliliters of benzene, milliliters of methanol, and five milliliters ofi acetic acid, is added 2.4 grams of zinc dust, and the whole is stirred vigorously for a period of four hours. The solid material is filtered off, washed with warm benzene, and the benzene washings added to the filtrate and the whole, filtrate and washings combined, is then washed successively with sixty milliliters of water, sixty milliliters of a saturated sodium bicarbonate solution and 6 25 milliliters of water. The resulting solution is thereupon dried and the solvent distilled to give crude 3-keto- 1 1;8-hydroxy-9// l0-seco-4,17(20)-pregnadien-2l-oic acid methyl ester which is purified by recrystallization from hot ethyl acetate and Skellysolve B hexane hydrocarbons to yield essentially pure 3-keto-l1,6-hydroxy-9//l0-seco- 4,17(20)-pregnadien-2l-oic acid methyl ester.

A solution of two grams of 3-keto-llB-hydroxy-9/l l0- seco-4,l7(20)-pregnadien-21-oic acid methyl ester, two milliliters of pyrrolidine and 250 milliliters of benzene is heated at reflux temperature for a period of six hours, during which time the water formed in the reaction is removed from the reaction mixture by codistillation with benzene. The benzene is then removed by distillation under reduced pressure. The thus obtained residue is triturated in methanol to give percent of a compound which is recrystallized from ethyl acetate and Skellysolve B to give 3-(N-pyrrolidyl)-llfl-hydroxy-W/ lO-seco- 3,5,l7(20)-pregnatrien-21-oic acid methyl ester.

Two grams of 3-(N-pyrrolidyl)-llfl-hydroxy-9//10- seco-3,5,l7(20)-pregnatrien-21-oic acid methyl ester, dissolved in 150 milliliters of benzene, is mixed at ten degrees centrigrade with two grams of lithium aluminum hydride in milliliters of ether by dropwise addition thereto. The resulting mixture is maintained at about ten degrees centrigrade for one-half hour. Thereafter fifty milliliters of water is added dropwise. The organic solvent layer is separated and the solvent removed. The thus obtained residue is triturated with ethyl acetate and thereafter recrystallized from methanol to give 3-pyrrolidyl l1,8,2l-dihydroxy-9//10-seco-3,5',17(20)-pregnatriene.

A suspension of one gram of 3-(N-pyrrolidyl)-ll}8,2ldihydroxy 9// l0 seco-3,5,l7(20)-pregnatriene in milliliters of methanol is heated at 35 to 40 degrees centigrade with seven milliliters of a five percent aqueous sodium hydroxide solution until solution is complete. The time of heating is less than ten minutes. The resulting solution is cooled, neutralized with acetic acid and the solvent distilled at reduced pressure. The residue thus obtained is mixed with water and repeatedly extracted with ether. The ether extract after evaporation of the solvent and recrystallization of the residue from ethyl acetate yields essentially pure 11,8,21-dihydroxy-9// l0- seco-4,17(20)-pregnadien-3-one.

A solution containing the 11,8,2l-dihydroxy-9/ l0- seco-4.l'7(20)-pregnadien-3-one in ten milliliters of pyridine and five milliters of acetic anhydride is allowed to stand at room temperature for a period of two hours. Thereafter the mixture is poured over 100 milliliters of ice water and the resulting precipitate collected on a filter. This precipitate is recrystallized from Skellysolve B hexane ethyl acetate mixtures to give essentially pure 115,21- diacetoxy-9/ liO-seco-4, l7 (20)-pregnadien-3-one.

To a solution of one gram of llfl,21-diacetoxy-9// 10- seco-4,l7(20)-pregnadien-3one in fifty milliliters of tertiary buty alcohol is added at room temperature nine milliliters of a 0.65 molar solution of hydrogen peroxide in sodium-dried tertiary butyl alcohol, followed by the dropwise addition of 75 milligrams of osmium tetroxide in eight milliliters of sodium-dried tertiary butyl alcohol over a period of eight hours. The resulting mixture is maintained at room temperature for an additional 48 hours and is thereafter worked up as follows: One gram of sodium sulfite dissolved in 25 milliliters of water is added, and after stirring for five minutes the resulting mixture is concentrated to about twenty milliliters by distillation at a pressure of about fifty millimeters of mercury absolute and the resulting concentrate then extracted with methylene chloride. The methylene chloride extract is dried over anhydrous sodium sulfite and chromatographed over 125 grams of synthetic magnesium silicate (Florisil). The column is developed with ethylene chloride containing increasing amounts of acetone. The fractions containing the 17a-hydroxy-11 8,21-diacetoxy-9// 10- Example 9.-17a-Hydr0xy 21 Acetoxy-9//10-Sec0-4- Pregnene-3,11,20-Trione (9//] O-Secocartisone Acetate) One-half gram of 11,8,l7a-dihydroxy-2l-acetoxy- 9// l0-seco-4-pregnene-3,ZO-dione i dissolved in five milliliters of acetic acid. To this solution is added 0.200 gram of chromic anhydride, dissolved in two milliliters of acetic acid. The solution is repeatedly shaken and maintained at room temperature (twenty to thirty degrees centigrade) for a period of four hours. Thereafter the material is poured onto fifty milligrams of ice and the resulting precipitate collected on filter paper, washed with water, and recrystallized from methanol to give essentially pure l7a-hydroxy-21-acetoXy-9//10-seco-4-pregnene-3 ,l1,20-trione.

The 9/ 10-secohydrocortisone and 9//10-secocor 'sone are prepared from the corresponding 9//10-sec0hydrocortisone acetate and 9//10-secocortisone acetate by bydrolyzing these compounds in methyl or ethyl alcohol in the presence of sodium or potassium hydroxide, methoxide, or ethoxide, under a nitrogen atmosphere at temperatures between fifteen and fifty degrees centigrade.

Other esters of 9//10-secohydrocortisone and 9//10- secocortisone are obtained by acylating the corresponding 1118,17a,2l trihydroxy-9// lO-seco-4-pregnene-3,ZO-dione and l7ct,21 dihydroxy 9// l0 seco-4-pregnene-3,1l,20- trione in conventional manner, such as by heating these compounds in pyridine solution with the acid chlorides, acid bromides or acid anhydrides of hydrocarbon carboxylic acids containing from one to eight carbon atoms, or other carboxylic acids containing from one to eight carbon atoms, to obtain the corresponding 1119,17ot-dihydroxy-21-acyloXy-9/ 10-seco-4-pregnene-3,20-dione and l7a-hydroxy-21-acyloxy-9//10-seco 4-pregnene-3,11,20- trione, wherein the acyloxy groups are for example, formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, benzoyloxy, [i-cyclopentyl-propionyloxy, dimethylacetoxy, trimethylacetoxy, phenylacetoxy, toluyloxy, anisoyloxy, gallyloxy, salicyloyloxy, cinnamyloxy, hemisuccinyloxy, hemitartaryloxy, dihydrogencitryloxy, hemimoleyloxy, hemifumaryloxy, crotonyloxy, acrylyloxy, fi-methylcrotonyloxy, cyclohexanecarbonyloxy, chloroacetoxy, dichloroacetoxy, trichloroacetoxy, bromoacetoxy, hemiquinolinoyloxy, nicotinyloxy, piperonyloxy, 2 furolyloxy, thioglycollyloxy, para-chlorobenzoyloxy, para-bromobenzoyloxy, meta-nitrobenzoyloxy, 3,5-dinitrobenzoyloxy, and the like.

It is to be understood that this invention is not to be limited to the exact details of operation or exact compounds shown and described as obvious modifications and equivalents will be apparent to one skilled in the art and the invention is therefore to be limited only by the scope of the appended claims.

We claim: 1. A compound having the following formula:

References ited in the file of this patent UNITED STATES PATENTS Hogg et a1. Apr. 26, 1955 OTHER REFERENCES Sarett et al.: J. Am. Chem. Soc., vol. 74, pages 4974-6 (1952).

Pincus et al.: The Hormones, vol. 111, page 607 1955).

A. A. Morton, Laboratory Technique in Organic Chemistry, McGraw-Hill, New York, 1938, pages 147 to 149; page 195.

(Copies of above in Library.) 

1. A COMPOUND HAVING THE FOLLOWING FORMULA: 